The role of melatonin in the molecular mechanisms underlying metaflammation and infections in obesity: A narrative review

Claudia Pivonello, Mariarosaria Negri, Roberta Patalano, Feliciana Amatrudo, Tatiana Montò, Alessia Liccardi, Chiara Graziadio, Giovanna Muscogiuri, Rosario Pivonello, Annamaria Colao, Claudia Pivonello, Mariarosaria Negri, Roberta Patalano, Feliciana Amatrudo, Tatiana Montò, Alessia Liccardi, Chiara Graziadio, Giovanna Muscogiuri, Rosario Pivonello, Annamaria Colao

Abstract

Obesity is a chronic condition whose management is a critical challenge for physicians. The scientific community has increased its focus on the molecular mechanisms involved in obesity etiopathogenesis to better manage patients with obesity and its associated complications. The tight connection between adipose tissue and the immune system has been demonstrated to play a crucial role in inflammation, and melatonin is important for circadian rhythm regulation and metabolic homeostasis, in which it orchestrates several molecular mechanisms involved in obesity and associated inflammation. Melatonin also regulates innate and adaptive immunity; its antioxidant properties are linked to reduced predisposition to infection and weight gain in patients with obesity through the modulation of the immune response, which has a significant beneficial effect on inflammation and, consequently, on the metabolic state. Low melatonin levels have been linked to obesity, and melatonin supplementation can reduce body weight, improve metabolic profile, and ameliorate immune responses and pro-inflammatory stimuli. The role of melatonin in obesity is mainly related to improved oxidative stress signaling, modulation of adipokine secretion, and a switching from white-to-brown adipose tissue phenotype and activity. Moreover, the role of melatonin in obesity modulation by controlling circadian rhythm has recently emerged as a pivotal mechanism for lipid and glucose metabolism dysfunction in adipose, muscle, and liver tissues. Melatonin may also regulate the immune system by acting directly on thymus morphology and activity as well as by modulating oxidative stress and inflammatory states during infections. The tight association between melatonin and immune response regulation is coordinated by Toll-like receptors, which are rhythmically expressed during the day. Their expression may be strongly modulated by melatonin as their signaling is highly inhibited by melatonin. The current review summarizes studies of melatonin-induced mechanisms involved in infection regulation, particularly the modulation of obesity-associated inflammation and systemic complications.

Keywords: infections; melatonin; metaflammation; obesity.

Conflict of interest statement

The authors declare no conflict of interest.

© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.

Figures

FIGURE 1
FIGURE 1
Melatonin regulation of peripheral clocks. All vertebrates synthesize and release melatonin through the pineal gland in a circadian‐dependent manner that has a classical peak during the night and is suppressed during the day. The nocturnal synthesis and release of melatonin are highly controlled by the master clock residing in the suprachiasmatic nucleus (SCN) through a fine molecular mechanism that is inhibited by light exposure. In turn, melatonin synchronizes peripheral clocks by acting at different levels and regulating several physiological functions. When melatonin synthesis and secretion are deregulated and/or desynchronized due to loss of master clock function, there is misalignment of peripheral clocks and a failure of physiological function control. Illustrations created with BioRender.com
FIGURE 2
FIGURE 2
Molecular mechanisms induced by melatonin in different peripheral targets. Melatonin entrains the expression of clock genes in hepatocytes, reduces lipid accumulation, and decreases hepatic steatosis by downregulating Fas, Pparγ, and Srebp1 gene expression in the liver. The action of melatonin on white adipocytes induces a switch to the brown adipocyte phenotype, activating thermogenic action through stimulation of Ucp‐1, Irisin, and Pparγ gene expression. The lack of melatonin action in muscle cells induces a loss of the physiological rhythm of glucose. Illustrations created with BioRender.com
FIGURE 3
FIGURE 3
Metabolic and immune effects of melatonin in rodent models. High‐fat diet (HFD) mice exposed to constant light for 24 h showed dysregulated circadian rhythms accompanied by increased body weight. On the hepatic level, mice displayed upregulated levels of Fas and Srebp1 genes, which are associated with hepatomegaly and steatosis. These mice were also hyperglycemic and insulin resistant, and treatment with melatonin improved their metabolic profile by decreasing body weight and downregulating Fas and Srebp1 gene expression in the liver. Thus, hepatic steatosis decreased, and systemic insulin sensitivity and glycemia were improved. Pinealectomized rats exposed to constant light showed decreased levels of thymosin α1 and thymulin, which are important factors secreted by the thymus involved in the maturation of immune cells (B cells, T cells, and natural killer cells). Interestingly, melatonin supplementation in this rat model promoted the secretion of thymosin α1 and thymulin, thus improving cell‐mediated immunity. Illustrations created with BioRender.com
FIGURE 4
FIGURE 4
Possible mechanistic routes in which melatonin affects the infection process. Melatonin can reduce body weight and thus contributes to the reduction of visceral adipose tissue, which is the main source of inflammatory signals. In addition, melatonin has been reported to have antioxidant properties that reduce both reactive oxygen species (ROS) and nitrogen species. The reduction of low‐grade inflammation, along with antioxidant effects, contributes to an improved insulin resistance at both hepatic and muscle sites. All these mechanisms result in an improvement in both innate and cellular immunity to infections. Illustrations created with BioRender.com

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